Project number 4 Schistosoma japonicum: Genomics, Post-Genomics, and Genetic Diversity. Within the overarching theme of "Emerging Helminthiases in China: Genetic Diversity, Transmission Dynamics, and the Impact of Environmental Changes" of this TMRC submission, this project focuses on the genomics of Schistosoma japonicum, and genetic heterogeneity of S. japonicum in China. The genomics component will prelude wide scale postgenomics research planned as a major future effort of the TMRC in collaboration with the Chinese National Human Genome Centre. Because wide evolutionary and biological divergence exists between S. japonicum and S. mansoni, S. mansoni may not be a suitable paradigm for the genus Schistosoma and, in particular, for the Asian schistosomes. This is of specific concern for our understanding of the biology, genetics and ecology of S. japonicum since much of the collaborative efforts of workers in the burgeoning field of schistosome genomics are focused on S. mansoni. Moreover, it is probable that extensive genetic divergence has taken place within the S. japonicum population, reflected now in differences in modes of transmission in China and in the host range of both the mammalian definitive and snail intermediate hosts. The nature and extent of these genetic changes remain unclear and uncertain. Because of the expected impact of the Three Gorges Dam on the ecology, endemicity and epidemiology of schistosomiasis japonica in southern China, and because of the importance of a more comprehensive understanding of schistosome genomics and genetics to these issues, it is now timely that investigations be focused on the nature of the S. japonicum genome and its genetic diversity. We propose to pursue three specific aims in order to address this goal. 1. Comparative genomics analysis of S. japonicum and S. mansoni, taking advantage of massive and rapid increases in the numbers of expressed sequence tags from Chinese S. japonicum that will be available through an exciting collaboration with the Chinese National Human Genome Center. (This collaboration will deliver more than 100,000 ESTs in the first year, enough for complete coverage of the entire transcriptome of adult S. japonicum!) 2. From the newly discovered genes, characterization of candidate molecules likely to be of interest to our TMRC group, and others, particularly secretory/excretory and surface proteins, as intervention and diagnostic targets. 3. Focusing on genes of interest, explore for genetic diversity the populations of S. japonicum involved in different modes of transmission, especially of parasites from Yunnan and Sichuan that are ecologically differentiated from those of the lower Yangtze River basin.